+

WO2010076764A1 - Composés inhibiteurs irréversibles de l'egfr dotés d'une activité antiproliférative - Google Patents

Composés inhibiteurs irréversibles de l'egfr dotés d'une activité antiproliférative Download PDF

Info

Publication number
WO2010076764A1
WO2010076764A1 PCT/IB2009/055980 IB2009055980W WO2010076764A1 WO 2010076764 A1 WO2010076764 A1 WO 2010076764A1 IB 2009055980 W IB2009055980 W IB 2009055980W WO 2010076764 A1 WO2010076764 A1 WO 2010076764A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogen
derivative
formula
alkyl
vii
Prior art date
Application number
PCT/IB2009/055980
Other languages
English (en)
Inventor
Marco Mor
Fabrizio Bordi
Caterina Carmi
Stefano Vezzosi
Alessio Lodola
Pier Giorgio Petronini
Roberta Alfieri
Andrea Cavazzoni
Original Assignee
Universita' Degli Studi Di Parma
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universita' Degli Studi Di Parma filed Critical Universita' Degli Studi Di Parma
Publication of WO2010076764A1 publication Critical patent/WO2010076764A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms

Definitions

  • the present invention relates to the synthesis and pharmacological activity of new compounds usable as irreversible inhibitors of the epidermal growth factor receptor (EGFR).
  • EGFR epidermal growth factor receptor
  • the epidermal growth factor receptor family comprises four transmembrane receptors (erbB1/EGFR, erbB2/HER2, erbB3/HER3 and erbB4/HER4) comprising an extracellular portion which binds to the ligand (except erbB2), a transmembrane domain and an intracellular domain with tyrosine kinase activity (except erbB3).
  • EGFR epidermal growth factor
  • TGF- ⁇ transforming growth factor ⁇
  • EGFR is over-expressed or present in a constitutively activated form in various solid tumors of epithelial origin, such as non small cell lung carcinoma (NSCLC), and its involvement in tumor onset and progression is often associated with a negative prognosis (Voldborg, B. R.; Damstrup, L.; Spng-Thomsen, M.; Poulsen, H. S. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann. Oncol. 1997, 8, 1197-1206; Ritter, C. A.; Artega, C. L. The epidermal growth ' factor receptor tyrosine kinase: a promising therapeutic target in solid tumors. Semin. Oncol.
  • Gefitinib (Iressa®; AstraZeneca) and erlotinib (Tarceva®; Genentech), approved for the treatment of lung cancers (NSCLC), are 4-anilinoquinazoline compounds active as reversible EGFR inhibitors, whose formula is given in Figure 1a.
  • the 4- anilinoquinazoline derivatives potently and selectively inhibit the EGFR-tyrosine kinase activity by binding to an ATP site in the intracellular domain of the receptor (Wissner, A.; Berger, D. M.; Boschelli, H. D.; Floyd M. B.; Greenberger, L. M.; Gruber, B. C; Johnson, B.
  • gefitinib and erlotinib have proved to be very useful in the treatment of specific patient groups (Asian women, non-smokers, carriers of specific EGFR mutations), clinical practice has highlighted primary and acquired resistance phenomena which limit their usefulness (Fukuoka, M.; Yano, S.; Giaccone, G.; Tamura, T.; Nakagawa, K.; Douillard, J.; Nishiwaki, Y.; Vansteenkiste, J.; Kudoh, S.; Rischin, D.; Eek, R.; Horai, T.; Noda, K; Takata, I.; Smit, E.; Averbuch, S.; Macleod, A.; Feyereislova, A; Dong, R.; Baselga, J.
  • This class comprises for example the irreversible inhibitors PD 168393, compound 5a shown in Figure 1b (Fry, D. W.; Briges, A. J.; Denny, W. A.; Doerthy, A.; Greis, K. D.; Hicks, J. L.; Hook, K. E.; Keller, P. R.; Leopold, W. R.; Loo, J. A.; McNamara, D. J.; Nelson, J. M.; Sherwood, V.; Smail, J.
  • Binding irreversibly to EGFR confers considerable advantages to this inhibitor class over the reversible inhibitors gefitinib and erlotinib, namely: (a) they maintain a prolonged effect over time: once the irreversible inhibitor is covalently bound to the enzyme the effect persists until EGFR is newly resynthesized; (b) they have a better selectivity of action: the irreversible inhibitors covalently bind to a cysteine residue adjacent to the ATP-binding site entrance (Cys773 in EGFR, Cys784 in erbB2 and Cys778 in erbB4), which unequivocally characterizes the erbB family in relation to other kinases; (c) they are able to overcome secondary resistance to treatment with gefitinib and erlotinib.
  • the irreversible EGFR inhibitors described in the literature are therefore characterized by a 4-anilinoquinazoline or a 4-anilinoquinoline-3-carbonitrile core, to which is bound the reactive group able to form a covalent bond with the molecular target by means of Michael-type 1,4 addition reactions, or nucleophilic substitution reactions, with the cysteine residues at the catalytic site of the target protein.
  • the Michael acceptor groups within known irreversible inhibitors such as acrylamides, propargilamides and vinyl sulphonamides, have an intrinsic tendency to react with certain amino acids (preferentially cysteine); although the remaining portion of the molecule should confer reaction selectivity, i.e. would make much less probable those reactions that form adducts with proteins other than EGFR, there may be side-effects due to unwanted reactions. For this reason, it is important that any new therapeutic strategy should not be entrusted to compounds with said chemical characteristics, even promising ones such as canertinib, but should be backed-up by researching whether the inhibitor's chemical structure can be varied so as to have knowledge of the structure-activity relationship and hence obtain alternative solutions to possible problems that may emerge from clinical studies.
  • the object of the present invention is therefore to provide compounds which can be used as irreversible inhibitors with high reaction selectivity. Summary of the invention Said object is achieved by means of a derivative of formula (VII)
  • R 27 , R 28 are, independently of each other, hydrogen, (CrC 6 )alkyl, (CH 2 )n-COOR 33 , (CH 2 )n-CONR 3 3R34, (CH 2 )n-NR 3 3R34 or (CH 2 ) n -morpholine; or
  • N N-R 27 -NR 27 R 28 is selected from morpholine, piperidine and ⁇ — ' , where R33. R34 are, independently, hydrogen or (CrC 6 )alkyl;
  • R 29 is hydrogen or (Ci-C 6 )alkyl
  • R 30 is hydrogen or -OR 35 , where R35 is (CrC 6 )alkyl, (CH 2 ) n -NR 3 3R34, (CH 2 ) n - piperidine or (CH 2 ) n -morpholine, where R 33 , R 34 are, independently, hydrogen or
  • Y is a nitrogen atom or a carbon atom substituted by a cyano group
  • R 3 i and R 32 are, independently of each other, hydrogen, bromine, chlorine, fluorine, ethinyl or methyl;
  • X is hydrogen, bromine, chlorine, fluorine or -O(CH 2 ) n -Q;
  • Q is an aryl or heteroaryl group, optionally substituted by one or more substituents selected, independently of each other, from hydrogen, chlorine, fluorine, the CF 3 radical or -NO 2 ; n is a whole number selected from 0, 1, 2, 3, 4, 5, or 6.
  • the derivative of the invention is usable as an irreversible inhibitor of the tyrosine kinase activity associated with the epidermal growth factor receptor (EGFR).
  • the compounds of the present invention are formed of groups, not themselves reactive towards cysteine, being linked through an amide bond to the 6-amino-4-anilinoquinazoline or 6-amino-4-anilino-3- cyanoquinoline core responsible for interacting with the molecular target.
  • the amides derived from ⁇ -aminocarboxyls are the object of the present invention because, following ⁇ -elimination reactions, they generate acrylamide derivatives able to produce Michael-type 1,4 addition reactions with cysteine.
  • the present invention relates to their preparation and their use as antitumor drugs in the treatment of solid tumors of epithelial origin such as non small cell lung carcinoma (NSCLC) with particular reference to tumors having developed secondary resistance to reversible EGFR inhibitors such as gefitinib and erlotinib.
  • NSCLC non small cell lung carcinoma
  • Figures 1a and 1b show the structures of the EGFR inhibitors known in the literature, i.e. reversible inhibitors (gefitinib and, erlotinib, Figure 1a) and irreversible inhibitors (PD168393 and canertinib, Figure 1b);
  • Figures 2a and 2b show the effect of compound 21a (UPR1157) of the invention on the autophosphorylation levels of EGFR in A431 cells. The cells were incubated for 1 hour with various concentrations of compound 21a, then stimulated with EGF immediately after incubation (Figure 5a) or 8 hours after removal of the compound ( Figure 5b).
  • R 2 7, R 2 s are, independently of each other, hydrogen, (Ci-C 6 )alkyl, (CHa) n -COOR 33 , (CH 2 )n-CONR 33 R 34 , (CH 2 ) n -NR 33 R 34 or (CH 2 ) n -morpholine;
  • R 2 8 is selected from morpholine, piperidine, and ⁇ — / , where R 33 ,
  • R 34 are, independently, hydrogen or (Ci-C 6 )alkyl
  • R 2 9 is hydrogen or (CrC 6 )alkyl
  • R30 is hydrogen or -OR35, where R 35 is (C r C 6 )alkyl, ( C H 2 ) n -N R 33 R 34 , (CH 2 ) n - piperidine or (CH 2 ) n -morpholine, where R 33 , R 34 are, independently, hydrogen or
  • Y is a nitrogen atom or a carbon atom substituted by a cyano group
  • R 3 i and R 32 are, independently of each other, hydrogen, bromine, chlorine, fluorine, ethinyl or methyl;
  • X is hydrogen, bromine, chlorine, fluorine or -0(CH 2 ) n -Q;
  • Q is an aryl or heteroaryl group, optionally substituted by one or more substituents selected, independently of each other, from hydrogen, chlorine, fluorine, the CF 3 radical or -NO 2 ; n is a whole number selected from O, 1, 2, 3, 4, 5, or 6.
  • aryl group is intended a monocyclic or polycyclic fused aromatic ring composed only of carbon atoms with a completely conjugated system of ⁇ -electrons;
  • heteroaryl group is intended a monocyclic or polycyclic fused system having within the ring one or more heteroatoms such as nitrogen, oxygen, sulphur, characterized by a completely conjugated system of ⁇ -electrons;
  • the derivative of the invention is usable as an irreversible inhibitor of tyrosine kinase activity associated with the epidermal growth factor receptor (EGFR).
  • EGFR epidermal growth factor receptor
  • (CrC 6 )alkyl is preferably an alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl and tert-butyl, n-pentyl, n-hexyl.
  • (CH 2 )n-COOR 3 3, (CH 2 ) n -CONR 33 R 34 , (CH 2 ) n -NR 33 R 34 or (CH 2 ) n - morpholine in the aforesaid formula preferably represent linear methylene, ethylene, propylene, butylene, pentylene or hexylene alkyl chains which operate as alkyl spacers and bind carboxyl, amido, or amino groups to the terminal carbon.
  • R 27 , R28 are methyl, ethyl, (CH 2 ) n -COOR 33 , (CH 2 )n-CONR 33 R 3 4, (CH 2 ) n -NR 33 R 34 ,
  • R 2 S is selected from piperidine, morpholine, ⁇ /-methylpiperazine, more preferably R 33, R 34 are methyl or ethyl,
  • R 29 is hydrogen and R 30 is hydrogen or -OR 35 , where R 35 is methyl, ethyl, (CH 2 ) n -morpholine.
  • R 3 i and R 32 are preferably hydrogen, chlorine or fluorine
  • X is hydrogen, fluorine or -O-(CH 2 ) n -Q and Q is preferably 3-fluorophenyl or 2- pyridine.
  • n is preferably a whole number selected in the range from 1 to 4. More preferably the compounds of the invention are selected from the group consisting of:
  • the compounds of the present invention are characterized by the presence of groups, not themselves reactive towards nucleophiles, but following ⁇ -elimination reactions they give compounds capable to form covalent chemical bonds with bionucleophiles such as cysteine residues; said groups are bound through an amide bond to a moiety able to selectively ensure the interaction between the described compounds and EGFR.
  • the association between the two halves means that reactions giving rise to covalent adducts with proteins other than EGFR are unlikely to occur, thus resulting in the selective inhibition of the enzyme which recognizes with high affinity the recognition moiety and simultaneously places an amino acid, able to react with the reactive moiety, in a sterically favourable position.
  • the compounds of the present invention comprise carboxyl derivatives of groups, not themselves reactive towards nucleophiles, but following ⁇ -elimination reactions they generate acrylamide derivatives which are reactive towards bionucleophiles.
  • the compounds belonging to the described series have demonstrated irreversible inhibitory activity on EGFR autophosphorylation and antiproliferative activity both on a cell line sensitive to treatment with reversible EGFR inhibitors (human ovarian carcinoma A431, hyperexpressing EGFR), and on a cell line resistant to treatment with reversible EGFR inhibitors (human lung carcinoma H 1975, carrier of a T790M mutation in the intracellular part of the receptor responsible for resistance to gefitinib treatment). Furthermore, the compounds of the invention have demonstrated inhibitory activity on the autophosphorylation of both EGFR and erbB2 in cell line H1975.
  • the compounds of the invention can be prepared using conventional methods or techniques in organic chemistry. Some synthesis paths will be described below (schemes 1, 8, 9).
  • the intermediate used for the synthesis of the compounds of the present invention is the 4-anilinoderivative (5) or (29) depending on whether Y is respectively nitrogen or carbon bound to a -CN substituent, having an amino group -NH 2 in position 6.
  • the intermediate (5) was synthesized according to the path described in scheme 1 or as reported in the literature (Rewcastle, G. W.; Denny, W. A.; Bridges, A. J.; Zhou, H.; Cody, D. R.; McMichael, A.; Fry, D. W.
  • Tyrosine kinase inhibitors synthesis and structure-activity relationships for 4-[(phenylmethyl)amino]- and 4- [(phenylamino)quinazolines as potent adenosine 5'-triphosphate binding site inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor. J. Med. Chem. 1995, 38, 3482-3487;. Domarkas, J.; Dudouit, F.; Williams, C; Qiyu, Q.; Banerjee, R.; Brahimi, F.; Jean-Claude, B. J. The combi-targeting concept: synthesis of stable nitrosureas designed to inhibit the epidermal growth factor receptor (EGFR). J. Med.
  • Reagents in step (i) HaSCVformic acid, reflux; in step (ii) SOCI 2 , dioxane, reflux; in step (iii) 3-substituted aniline, 2-propanol, 6O 0 C; in step (iv) Fe/acetic acid/ethanol/H 2 O, reflux.
  • the compounds (21 ) of Formula (VII) are synthesized as described in scheme 8.
  • the amine (5) is acylated with 3-chloropropionyl chloride (19) to obtain the intermediate 3-chloropropionamide (20).
  • Subsequent treatment with the suitable secondary amine gives the product 3-aminopropionamide (21) in a good yield.
  • Reagents in step (i) reflux; in step (ii) NHR27R28. NaI, ethanol, reflux.
  • the 6-amino-4-anilino-3-cyanoquinoline intermediate (29) used for synthesizing the compounds of the present invention was obtained as described in scheme 9 or as reported in the literature (Tsou, H.-R.; Overbeek-Klumpers, E. G.; Hallet, WA; Reich, M. F.; Brawner Floyd, M.; Johnson, B. D.; Michalak, R. S.; Nilakantan, R.; Discafani, C; Golas, J.; Rabindran, S. K.; Shen, R.; Shi, X.; Wang, Y.; Upeslacis, J.; Wissner, A.
  • Reagents in step (i) acetic anhydride, acetic acid, 6O 0 C; in step (ii) hydrogen, 10% Pd/C, ambient temperature; in step (iii) ethyl ethoxymethylene cyanoacetate, 90 0 C; in step (iv) dowtherm A mixture, 25O 0 C; in step (v) phosphorus oxychloride, diethylene glycol dimethyl ether, 100 0 C; in step (vi) substituted aniline, pyridine hydrochloride, isopropanol, reflux; in step (vii) dilute hydrochloric acid, reflux.
  • the compounds of the invention can contain stereogenic centres and can hence be prepared and/or isolated either as single stereoisomers or as enantiomeric or diastereoisomeric mixtures thereof. Both the aforesaid single stereoisomers, and the enantiomeric or diastereoisomeric mixtures thereof fall within the scope of the invention claimed herein.
  • the compounds of the invention contain a basic -NH- group which can form addition salts with acids, particularly with pharmaceutically acceptable acids.
  • the present invention relates to new 4-anilinoquinazoline derivative compounds usable as irreversible EGFR inhibitors with antiproliferative activity which can be used for the treatment of disorders connected to an altered EGF receptor activity.
  • the compounds of the present invention can be used as therapeutic agents for the treatment of diseases such as different tumor forms of epithelial origin where there is an altered functioning of receptors with tyrosine kinase activity of the EGFR family.
  • the invention therefore concerns the use of said compounds in the treatment of diseases in which there is an altered functioning of receptors with tyrosine kinase activity of the EGFR family.
  • the invention hence concerns the use of said compounds for treating different tumor forms of epithelial origin.
  • the invention also concerns the use of said compounds in the treatment and prevention of cell proliferation disorders such as papilloma, blastoglioma, Kaposi's sarcoma, melanoma, lung cancer, ovarian cancer, prostate cancer, breast cancer, astrocytoma, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukaemia, lymphoma.
  • ⁇ -aminocarboxyl derivatives of the invention following a ⁇ - elimination reaction with formation of the corresponding acrylamide derivative, can interact with nucleophiles by means of Michael 1 ,4-addition reactions.
  • Example 2 A/-(4-(3-chloro-4-(2-piridinylmethoxy)anilino)-3-cva ⁇ o-7-ethoxyquinolin-6-v ⁇ -3- (dimethylamino)propanamide (21b) a) Preparation of the compound N-(4-(3-chloro-4-(piridin-2- ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-chloropropanamide 20b)
  • Example 6 ⁇ /-(4-(3-bromoanilino)quinazolin-6-yl)-3-(4-methylpiperazin-1-v ⁇ propionamide (21f)
  • the compound of the title was obtained.
  • the product was purified by chromatography (SiO 2 , eluent CH 2 CI 2 /CH 3 OH from 95:5), and crystallized from ethyl ether. A solid white product was obtained, yield 70%; m.p.
  • Compound 21a was prepared in example 1.
  • Compounds 5a, PD168393 and gefitinib were used as the known derivatives, they having been synthesized as described in the literature.
  • the compounds were dissolved in DMSO at a concentration of 10 mM then diluted in the culture medium to obtain final DMSO concentrations which were always lower than 0.1% (v/v).
  • the control samples were treated with the same amount of DMSO. Cell cultures.
  • the human carcinoma cell lines A431 (uterine cervix) and H1975 (lung carcinoma) were cultivated, respectively, in D-MEM (Dulbecco's modified Minimum Essential Medium) with 4.5 g/l of glucose, and RPMI, both completed with 10% fetal calf serum (FCS) and the addition of the antibiotics penicillin (10 Ill/ml) and streptomycin (100 ⁇ g/ml).
  • D-MEM Dulbecco's modified Minimum Essential Medium
  • FCS fetal calf serum
  • the A431 cells express high levels of non- mutant EGFR whereas the H1975 cells bear the mutation T790M, responsible for the diminished sensitivity to gefitinib treatment, in the intracellular domain of the receptor.
  • the cultures were temperature controlled at 37 0 C in air saturated with water vapour and enriched with 5% CO2.
  • Equal aliquots of cell lysate were analyzed by Western blot, utilizing specific phosphorylated anti-tyrosine antibodies (Cavazzoni, A.; Petronini, P.G.; Galetti, M.; Roz, L.; Andriani, F.; Carbognani, P.; Rusca, M.; Fumarola, C; Alfieri, R.; Sozzi, G. Dose-dependent effect of FHIT-inducible expression in Calu-1 lung cancer cell line. Oncogene 2004, 23, 8439-46).
  • a second set of cells was incubated for 1 hour with the stated concentrations of compound following which the inhibitor was removed from the medium and the cells were subjected to a series of washes for 8 hours before being stimulated with EGFR (0.1 ⁇ g/ml) for 5 minutes. The cells were then analyzed by Western blot, as previously described. Test for cell proliferation inhibition.
  • MTT viability assay (3(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide in formazan; Sigma, Dorset, UK) as previously described (Cavazzoni, A.; Petronini, P.G.; Galetti, M.; Roz, L.; Andriani, F.; Carbognani, P.; Rusca, M.; Fumarola, C; Alfieri, R.; Sozzi, G. Dose-dependent effect of FHIT-inducible expression in Calu-1 lung cancer cell line. Oncogene 2004, 23, 8439-46), after the cells had been incubated for 72 hours with the stated concentrations of the compound.
  • the compound 21a (UPR1157) exhibited a ⁇ -aminocarboxyl group which, in the presence of a base that stabilized the enol form of the amide, could undergo ⁇ - elimination reaction with formation of the corresponding acrylamide derivative able to produce a Michael-type 1,4 addition reaction with a bionucleophile such as cysteine.
  • the compound 21a demonstrated irreversible inhibition of EGFR autophosphorylation (Figure 2a) with the effect remaining for 8 hours after removal of the compound from the medium ( Figure 2b).
  • the compound 21a was also able to inhibit proliferation of A431 cells (IC 50 0.16 ⁇ M, Table 1) and H 1975 cells (IC 50 3.04 ⁇ M, Figure 3 and Table 1). In the H1975 model, being resistant to gefitinib treatment, 21a inhibited autophosphorylation of EGFR and erbB2, and reduced phosphorylation of erbB3, Akt and MAPK, involved in signal transduction (Figure 4).
  • Table 1 IC 50 values ( ⁇ M) for inhibition of EGFR autophosphorylation and A431 and H1975 cell proliferation
  • PD 168393 0.008 0.121 0.203 0.591 a Concentration that inhibits 50% of EGFR autophosphorylation activity in A431 cells incubated for 1 hour with various concentrations of the compound, then immediately after stimulated with EGF. b Concentration that inhibits 50% of EGFR autophosphorylation activity in A431 cells incubated for 1 hour with various concentrations of the compound, then stimulated with EGF 8 hours after removal of the inhibitor from the medium. c Concentration that inhibits 50% of A431 cell proliferation. The cell proliferation is determined using the MTT viability assay after treatment for 72 hours with compound concentrations comprised between 0.01 and 10 ⁇ M. d Concentration that inhibits 50% of the proliferation of H1973 cells. The cell proliferation is determined using the MTT viability assay after treatment for 72 hours with compound concentrations comprised between 0.01 and 20 ⁇ M.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur un dérivé de formule (VII), dans laquelle R27 et R28 représentent chacun, indépendamment de l'autre, un atome d'hydrogène, un groupe alkyle en C1-C6), (CH2)n-COOR33, (CH2)n-CONR33R34, (CH2)n-NR33R34 ou (CH2)n-morpholine; ou NR27R28 représente -NN-R27 choisi parmi la morpholine, la pipéridine et la formule (VIII), où R33 et R34 représentent chacun, indépendamment, un atome d'hydrogène ou un groupe alkyle en C1-C6; R29 représente un atome d'hydrogène ou un groupe alkyle en C1-C6; R30 représente un atome d'hydrogène ou -OR35, où R35 représente un groupe alkyle en C1-C6, (CH2)n-NR33R34 ou (CH2)n-pipéridine ou (CH2)n-morpholine, où R33 et R34 représentent chacun, indépendamment, un atome d'hydrogène ou un groupe alkyle en C1-C6; Y représente un atome d'azote ou un atome de carbone substitué par un groupe cyano; R31 et R32 représentent chacun, indépendamment de l'autre, un atome d'hydrogène, de brome, de chlore, de fluor, un groupe éthynyle ou méthyle; X représente un atome d'hydrogène, de brome, de chlore, de fluor ou -O(CH2)n-Q; Q représente un groupe aryle ou hétéroaryle, éventuellement substitué par un ou plusieurs substituants choisis chacun, indépendamment des autres, parmi un atome d'hydrogène, de chlore, de fluor, le radical CF3 ou -NO2; n représente un nombre entier choisi parmi 0, 1, 2, 3, 4, 5 ou 6. Les dérivés de l'invention sont utilisés comme inhibiteurs irréversibles de l'EGFR dotés d'une activité antiproliférative.
PCT/IB2009/055980 2008-12-29 2009-12-29 Composés inhibiteurs irréversibles de l'egfr dotés d'une activité antiproliférative WO2010076764A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT002336A ITMI20082336A1 (it) 2008-12-29 2008-12-29 Composti inibitori irreversibili di egfr con attivita' antiproliferativa
ITMI2008A002336 2008-12-29

Publications (1)

Publication Number Publication Date
WO2010076764A1 true WO2010076764A1 (fr) 2010-07-08

Family

ID=41168672

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/055980 WO2010076764A1 (fr) 2008-12-29 2009-12-29 Composés inhibiteurs irréversibles de l'egfr dotés d'une activité antiproliférative

Country Status (2)

Country Link
IT (1) ITMI20082336A1 (fr)
WO (1) WO2010076764A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103275019A (zh) * 2013-04-26 2013-09-04 浙江工业大学 4-[3-氯-4-取代苯胺基]-6-取代甲氧基甲酰氨基喹唑啉类化合物及制备和应用
WO2014089546A1 (fr) * 2012-12-09 2014-06-12 The Scripps Research Institute Sondes covalentes ciblées et inhibiteurs de protéines contenant des cystéines sensibles à l'oxydoréduction
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2020245208A1 (fr) 2019-06-04 2020-12-10 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de cd9 en tant que biomarqueur et en tant que biocible dans la glomérulonéphrite ou la glomérulosclérose
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003050090A1 (fr) * 2001-11-27 2003-06-19 Wyeth Holdings Corporation 3-cyanoquinolines en tant qu'inhibiteurs de kinases egf-r et her2
WO2006071017A1 (fr) * 2004-12-29 2006-07-06 Hanmi Pharm. Co., Ltd. Dérivés de quinazoline employés dans l'inhibition de la croissance des cellules cancéreuses et méthodes de synthèse desdits dérivés

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU725533B2 (en) * 1996-04-12 2000-10-12 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
TW436485B (en) * 1997-08-01 2001-05-28 American Cyanamid Co Substituted quinazoline derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003050090A1 (fr) * 2001-11-27 2003-06-19 Wyeth Holdings Corporation 3-cyanoquinolines en tant qu'inhibiteurs de kinases egf-r et her2
WO2006071017A1 (fr) * 2004-12-29 2006-07-06 Hanmi Pharm. Co., Ltd. Dérivés de quinazoline employés dans l'inhibition de la croissance des cellules cancéreuses et méthodes de synthèse desdits dérivés

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
ALLEN, L. F.; EISEMAN, I. A.; FRY, D. W.; LENEHAN, P. F.: "CI-1033, an irreversible pan-erbB receptor inhibitor and its potential application for the treatment of breast cancer", SEMIN. ONCOL., vol. 30, 2003, pages 65 - 78
BLAIR, J. A.; RAUH, D.; KUNG, C.; YUN, C.-H.; FAN, Q.-W.; RODE, H.; ZHANG, C.; ECK, M. J.; WEISS, W. A.; SHOKAT, K. M.: "Structure-guided development of affinity probes for tyrosine kinases using chemical genetics", NATURE CHEM. BIOL., vol. 3, 2007, pages 229 - 238, XP003035091, DOI: doi:10.1038/NCHEMBIO866
BRIDGES, A. J.; ZHOU, H.; CODY, D. R.; REWCASTLE, G. W.; MCMICHAEL, A.; SHOWALTER, H. D. H.; FRY, D. W.; KRAKER, A. J.; DENNY, W.: "Tyrosine Kinase Inhibitors. 8. An Unusually Steep Structure-Activity Relationship for Analogues of 4-(3-Bromoaniiino)-6,7-dimethoxyquinazo)ine (PD 153035), a.Potent Inhibitor of the Epidermal Growth Factor Receptor", J. MED. CHEM., vol. 39, 1996, pages 267
CARTER, T. A.; WODICKA, L. M.; SHAH, N. P.; VELASCO, A. M.; FABIAN, M. A.; TREIBER, D. K.; MILANOV, Z. V.; ATTERIDGE, C. E.; BIGGS: "Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases", PROC. NATL. ACAD. SCI. U.S.A., vol. 102, 2005, pages 11011 - 11016, XP002440841, DOI: doi:10.1073/pnas.0504952102
CAVAZZONI, A.; PETRONINI, P.G.; GALETTI, M.; ROZ, L.; ANDRIANI, F.; CARBOGNANI, P.; RUSCA, M.; FUMAROLA, C.; ALFIERI, R.; SOZZI, G: "Dose-dependent effect of FHIT-inducible expression in Calu-1 lung cancer cell line", ONCOGENE, vol. 23, 2004, pages 8439 - 46
DOMARKAS, J.; DUDOUIT, F.; WILLIAMS, C; QIYU, Q.; BANERJEE, R.; BRAHIMI, F.; JEAN-CLAUDE, B. J.: "The combi-targeting concept: synthesis of stable nitrosureas designed to inhibit the epidermal growth factor receptor (EGFR)", J. MED. CHEM., vol. 49, 2006, pages 3444 - 3552
FRY, D. W.; BRIGES, A. J.; DENNY, W. A.; DOERTHY, A.; GREIS, K. D.; HICKS, J. L.; HOOK, K. E.; KELLER, P. R.; LEOPOLD, W. R.; LOO,: "Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor", PROC. NATL. ACAD. SCI. U.S.A., vol. 95, 1998, pages 12022 - 12027, XP002246246, DOI: doi:10.1073/pnas.95.20.12022
FUKUOKA, M.; YANO, S.; GIACCONE, G.; TAMURA, T.; NAKAGAWA, K.; DOUILLARD, J.; NISHIWAKI, Y.; VANSTEENKISTE, J.; KUDOH, S.; RISCHIN: "Multi-institutional randomized phase 11 trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer", J. CLIN. ONCOL., vol. 12, 2003, pages 2237 - 2246
MARESSO, A. W.; WU, R.; KEM, J. W.; ZHANG, R.; JANIK, D.; MISSIAKAS, D. M.; DUBAN, M. E.; JOACHIMIAK, A; SCHNEEWIND, O.: "Activation of inhibitors by sortase triggers irreversible modification of the active site", J. BIOL. CHEM., vol. 282, 2007, pages 23129 - 23139
PÉREZ-SOLER, R.; CHACHOUA, A.; HAMMOND, L. A.; ROWINSKY, E. K.; HUBERMAN, M.; KARP, D.; RIGAS, J.; CLARK, G. M.; SANTABARBARA, P.: "Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer.", J. CLIN. ONCOL., vol. 22, 2004, pages 3238 - 3247
RAYMOND, E.; FAIVRE, S.; ARMAND, J. P: "Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy", DRUGS, vol. 60, 2000, pages 15 - 23
REWCASTLE, G. W.; DENNY, W. A.; BRIDGES, A. J.; ZHOU, H.; CODY, D. R.; MCMICHAEL, A.; FRY, D. W.: "Tyrosine kinase inhibitors: synthesis and structure-activity relationships for 4-[(phenylmethyl)amino]- and 4-[(phenylamino)quinazolines as potent adenosine 5'-triphosphate binding site inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor", J. MED. CHEM., vol. 38, 1995, pages 3482 - 3487, XP002044372, DOI: doi:10.1021/jm00018a008
RITTER, C. A.; ARTEGA, C. L.: "The epidermal growth 'factor receptor tyrosine kinase: a promising therapeutic target in solid tumors", SEMIN. ONCOL., vol. 30, 2003, pages 993 - 1011
SALOMON, D. S.; BRANDT, R.; CIARDIELLO, F.; NORMANNO, N.: "Epidermal growth factor-related peptides and their receptors in human malignancies", CRIT. REV. ONCOL. HEMATOL., vol. 19, 1995, pages 183 - 232, XP009002902, DOI: doi:10.1016/1040-8428(94)00144-I
SMAILL, J. B.; REWCASTLE, G. W.; LOO, J. A.; GREIS, K. D.; CHAN, O. H.; REYNER, E. L.; LIPKA, E.; SHOWALTER, H. D. H.; VINCENT, P.: "Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions", J. MED. CHEM., vol. 43, 2000, pages 1380 - 1397, XP002599292, DOI: doi:10.1021/jm990482t
TRAXIER, P; BOLD, G.; FREI, J.; LANG, M.; LYDON, N.; METT, H.; BUCHDUNGER, E.; MEYER, T.; MUELLER, M.; FURET, P.: "Use of a Pharmacophore Model for the Design of EGF-R Tyrosine Kinase Inhibitors: 4-(Phenylamino)pyrazolo[3,4-d]pyrimidines", J. MED. CHEM., vol. 40, 1997, pages 3601, XP002497479, DOI: doi:10.1021/jm970124v
TSOU, H.-R.; OVERBEEK-KLUMPERS, E. G.; HALLET, W.A.; REICH, M. F.; BRAWNER FLOYD, M.; JOHNSON, B. D.; MICHALAK, R. S.; NILAKANTAN,: "Optimization of 6,7-Disubstituted-4-(arylamino)quinoline-3-carbonitriles as Orally Active, Irreversible Inhibitors of Human Epidermal Growth Factor Receptor-2 Kinase Activity", J. MED. CHEM., vol. 48, 2005, pages 1107 - 1131
VOLDBORG, B. R.; DAMSTRUP, L.; SPNG-THOMSEN, M.; POULSEN, H. S.: "Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials", ANN. ONCOL., vol. 8, 1997, pages 1197 - 1206, XP002953363, DOI: doi:10.1023/A:1008209720526
WELLS, A., EGF RECEPTOR. INT. J. BIOCHEM. CELL BIOL., vol. 31, 1999, pages 637 - 643
WISSNER, A.; BERGER, D. M.; BOSCHELLI, H. D.; FLOYD M. B.; GREENBERGER, L. M.; GRUBER, B. C.; JOHNSON, B. D.; MAMUYA, N.; NILAKANT: "4-Anilino-6,7- dialkoxyquinoline-3-carbonitrile Inhibitors of Epidermal Growth Factor Receptor Kinase and Their Bioisosteric Relationship to the 4-Anilino-6,7-dialkoxyquinazoline Inhibitors", J. MED. CHEM., vol. 43, 2000, pages 3244, XP002909029, DOI: doi:10.1021/jm000206a

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014089546A1 (fr) * 2012-12-09 2014-06-12 The Scripps Research Institute Sondes covalentes ciblées et inhibiteurs de protéines contenant des cystéines sensibles à l'oxydoréduction
CN103275019A (zh) * 2013-04-26 2013-09-04 浙江工业大学 4-[3-氯-4-取代苯胺基]-6-取代甲氧基甲酰氨基喹唑啉类化合物及制备和应用
CN103275019B (zh) * 2013-04-26 2016-05-18 浙江工业大学 4-[3-氯-4-取代苯胺基]-6-取代甲氧基甲酰氨基喹唑啉类化合物及制备和应用
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2020245208A1 (fr) 2019-06-04 2020-12-10 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de cd9 en tant que biomarqueur et en tant que biocible dans la glomérulonéphrite ou la glomérulosclérose
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation

Also Published As

Publication number Publication date
ITMI20082336A1 (it) 2010-06-30

Similar Documents

Publication Publication Date Title
EP3299369B1 (fr) Composé pyrido-azahétérocyclique, et procédé de préparation et utilisation correspondants
EP2439195B1 (fr) Dérivés de naphtalène carboxamide en tant qu'inhibiteurs de protéine kinase et d'histone désacétylase, procédés de préparation et utilisations
Wissner et al. Dual irreversible kinase inhibitors: quinazoline-based inhibitors incorporating two independent reactive centers with each targeting different cysteine residues in the kinase domains of EGFR and VEGFR-2
FI119933B (fi) Aniliinijohdoksia
JP4393196B2 (ja) 痴呆関連疾患、アルツハイマー病およびグリコーゲンシンターゼキナーゼ−３関連症状の治療におけるオキシインドール誘導体の使用
CN101687819B (zh) 外用剂
KR101762306B1 (ko) 암과 관련된 질환의 치료에 유용한 6,7-디알콕시 퀴나졸린 유도체
Yin et al. Design, synthesis and biological evaluation of novel EGFR/HER2 dual inhibitors bearing a oxazolo [4, 5-g] quinazolin-2 (1H)-one scaffold
JP2008542267A (ja) ３−シアノ−キノリンと、それにより製造される中間体とを調製する方法
WO2010076764A1 (fr) Composés inhibiteurs irréversibles de l'egfr dotés d'une activité antiproliférative
CZ339697A3 (cs) Chinazolinové deriváty, způsob jejich přípravy a farmaceutický prostředek, který je obsahuje
JP2009541460A (ja) ヒスタミンｈ４受容体と相互作用する縮合二環式化合物
Qi et al. Identification of novel N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas showing potent multi-tyrosine kinase inhibitory activities
EP1268487B1 (fr) Inhibiteurs tricyclique de la proteine kinase
Lin et al. Novel oxazolo [4, 5-g] quinazolin-2 (1H)-ones: dual inhibitors of EGFR and Src protein tyrosine kinases
Das et al. In vivo efficacy studies of novel quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors, in lung cancer xenografts (NCI-H1975) mice models
EP3102571B1 (fr) Pyrimidines substituées utiles en tant qu'inhibiteurs de kinase d'egfr-t790m
EP2833886A1 (fr) Quinoléines substituées en tant qu'inhibiteurs de tyrosine kinases de bruton
Yu et al. Novel 4-anilinoquinazoline derivatives featuring an 1-adamantyl moiety as potent EGFR inhibitors with enhanced activity against NSCLC cell lines
Sundriyal et al. Histone lysine methyltransferase structure activity relationships that allow for segregation of G9a inhibition and anti-Plasmodium activity
Ding et al. Discovery of ErbB/HDAC inhibitors by combining the core pharmacophores of HDAC inhibitor vorinostat and kinase inhibitors vandetanib, BMS-690514, neratinib, and TAK-285
Kaila et al. Identification of a novel class of selective Tpl2 kinase inhibitors: 4-Alkylamino-[1, 7] naphthyridine-3-carbonitriles
Malhotra et al. Novel amide analogues of quinazoline carboxylate display selective antiproliferative activity and potent EGFR inhibition
KR102629854B1 (ko) 단백질 키나제 저해제로서 유용한 피리도퀴나졸린 유도체
Hou et al. Design, synthesis and antitumor activity of novel 6, 7-dimethoxyquinazoline derivatives containing diaryl urea moiety

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09807636

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09807636

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载